Within the pharmaceutical industry and medical community, there is an ongoing interest in the development of new chemotherapeutics for the treatment of persons with various types of cancer. Great strides have been made in the treatment of certain types of cancer, whereas certain other cancers remain refractory to treatments that are currently available.
In general, most cancer treatments operate by destroying the cancerous cells or by inhibiting cellular proliferation. Unfortunately, most chemotherapeutic agents known to the art lack specific toxicity, in that they are toxic for dividing normal cells, as well as malignant cells. Consequently, persons undergoing a regimen of chemotherapy may suffer severe side effects or even death as a consequence of nonspecific cytotoxicity. Recently, biological preparations from natural sources (e.g., Taxol, which is derived from the yew tree) have shown promise as a new source of more specific chemotherapeutic agents.
We are currently experiencing a worldwide epidemic of acquired immune defiency syndrome (AIDS), a disease caused by the retrovirus human immunodeficiency virus (HIV). As of December, 1994, more than one million cases of AIDS had been reported to the World Health Organization (WHO). The WHO has estimated that actual AIDS cases as of 1994 totalled more than 4.5 million worldwide. An estimate by the WHO predicts that there will be 10 million AIDS cases and 30-40 million people infected with HIV worldwide by the year 2000.
The human immunodeficiency virus, a lentivirus, is a member of the Retroviridae family of retroviruses. This family includes other members that are causal agents of devastating disease of humans. For example, certain cancers are caused by oncornaviruses, oncogenic viruses that cause transformation of cells. Retroviruses are particularly refractory to treatment, largely because of their unique replication strategy.
Retroviruses are single-stranded RNA viruses. The virions of retroviruses include reverse transcriptase, an enzyme that catalyzes the synthesis of a single-stranded DNA molecule, using the single-stranded viral RNA as a template. Second strand synthesis, also catalyzed by reverse transcriptase, yields a double-stranded DNA provirus that integrates into the host's genome. In the case of lentiviruses such as HIV, the virus may lie dormant for a period of several years before becoming activated again.
The human immuondeficiency virus infects CD4+ T lymphocytes, cells that play an important role in combatting infections. Proliferation of HIV within the T cells results in destruction of the cells and interruption of the cells' normal function. As a consequence, people with AIDS are susceptible to opportunistic infections and the development of neoplasms.
Millions of dollars have been directed toward the development of drugs for the treatment of persons infected with the human immunodeficiency virus (HIV). One promising class of chemotherapeutics includes inhibitors of reverse transcriptase, an enzyme that is required for the replication of HIV and other members of the Retroviridae family of viruses.
What is needed in the art are chemotherapeutic agents that are specific for cancerous cells. Also needed in the art are novel drugs that can effectively inhibit reverse transcriptase.